[Botulinum toxin type A (Relatox) in transition from medication overuse to non-overuse status in patients with chronic migraine: a subgroup analysis of phase IIIb randomized single-blind multicenter active-controlled parallel-group trial]. / Botulinicheskii toksin tipa A (Relatoks) v preodolenii lekarstvennogo zloupotrebleniya u patsientov s khronicheskoi migren'yu: podgruppovoi analiz rezul'tatov mnogotsentrovogo prostogo slepogo randomizirovannogo sravnitel'nogo issledovaniya IIIb fazy.

OBJECTIVE: To access the effect of Relatox, the first Russian botulinum toxin type A, in patients with chronic migraine (CM) and medication overuse (MO). MATERIAL AND METHODS: In phase IIIb single-blind randomized multicenter active-controlled parallel-group study, patients with CM were randomized to once intramuscular injections of Relatox (n=101) or onabotulinumtoxin A injections - Botox (n=108). This subgroup analysis evaluated the percentage of patients who transition from medication overuse to non overuse status from baseline; mean changes in the number of headache days, migraine headache days, acute headache medication intakes days, headache intensity, proportion of patients who had a ≥50% reduction in headache days, proportion of the patients with severe (≥60) Headache Impact Test-6 score and with a severe (≥21) MIDAS score in a 28-day periods in each treatment among patients with baseline acute medication overuse via repeated measures. RESULTS: Of 209 patients with CM, 100% met medication overuse criteria. Relatox and Botox demonstrated significant improvement for overall least squares mean change in headache days, migraine headache days, headache intensity; and headache-related disability and quality of life in CM patients with baseline MO, without differences between the groups. 75% and 70% patients in the Relatox and Botox groups, respectively, achieved ≥50% reduction in headache days from baseline (OR 1.58, CI 95% 0.84; 3.02, p=0.155). Furthermore, Relatox and Botox significant reduced average medication overuse rates in patient with CM and MO at baseline. 62% of patients in the Relatox group and 48% of patients in the Botox group transitioned from medication overuse to non overuse status compared from baseline (OR 2.07, CI 95% 0.91; 4.62, p=0.044). Relatox group had greater reductions than the Botox group in the percentage of patients with acute migraine-specific medication (triptan) overuse (p=0.050). CONCLUSION: The results demonstrate highly prevalent of medication overuse among individuals with CM. This analysis provides evidence that the Russian botulinum toxin type A Relatox significantly improves measures of headache symptoms, quality of life and headache-related disability, and also significantly greater, compared to Botox, reduces migraine-specific medication consumption in patients with chronic migraine who overuse acute medications.

[Botulinum toxin type A (Relatox) in the treatment of chronic migraine in adults: results of phase IIIb, randomized, one-blind, multicenter, active-controlled, parallel-group trial]. / Botulinicheskii toksin tipa A (Relatoks) v lechenii khronicheskoi migreni u vzroslykh: rezul'taty mul'titsentrovogo prostogo slepogo randomizirovannogo sravnitel'nogo issledovaniya IIIb fazy.

OBJECTIVE: To access the efficacy and safety of the first Russian botulinum toxin type A (Relatox) as a headache prophylaxis in adult with chronic migraine (CM). MATERIAL AND METHODS: The randomized, one-blind, multicenter, active-controlled, parallel-group trial study involved 209 patients with CM aged from 19 to 65 years. The patients were randomized to injections of the Russian botulinum toxin type A - Relatox (n=101) or onabotulinumtoxinA injections - Botox (n=108). The duration of the study was 16 weeks, which included five visits of patients every 4 weeks. Relatox and Botox were injected once into seven muscle groups of the head and neck at a dose of 155-195 units. Primary efficacy variable was mean change from baseline in frequency of headache days after 12 weeks. Secondary efficacy variables were mean changes from the baseline to week 12 in frequency of migraine days, acute headache pain medication intakes days; headache intensity; proportion of patients achieving ≥50% reduction from baseline in headache days, the proportion of the patients with medication overuse, the proportion of the patients with severe (≥60) Headache Impact Test-6 score and with a severe (≥21) MIDAS score. RESULTS: Analyses demonstrated a large mean decrease from baseline in frequency of headache days, without statistically significant between-group differences Relatox vs Botox at week 12 (-10.89 vs -10.06; p=0.365) and at other time points. Significant differences from baseline were also observed for all secondary efficacy variables at all time points without differences between the groups. The proportion of patients achieving ≥50% reduction from baseline in headache days was 75.0% and 70% in the Relatox and Botox groups, respectively (OR, CI 95% 1.58 [0.84; 3.02], p=0.155). Adverse events (AE) occurred in 15.8% of Relatox patients and 15.7% of Botox patients (p=1.000). No unexpected AE were identified. CONCLUSION: The results demonstrate that the first Russian botulinum toxin type A (Relatox) is an effective prophylactic treatment for CM in adult patients. Relatox led to significant improvements from baseline in multiple measures of headache symptoms, headache-related disability and quality of life. For the first time, a comparative analysis of two botulinum toxin type A products in parallel groups showed no less (not inferior) efficacy and safety of Relatox relative to Botox in the treatment of CM in adults.

Alleviation of the Genotoxic Effect of Experimental Circulatory Brain Hypoxia in Rat Cornea under the Effect of Infrared Low-Level Laser Radiation.

Experimental modeling of oxidative stress was conducted by creating circulatory brain hypoxia, accompanied by development of free radical processes leading to genome instability through an example of anterior epithelial layer of rat cornea. We studied the influence of infrared low-level laser radiation (ILLLR) in the therapeutic dose and mode (pulse power 8 W, λ=0.89 µm). Exposure of animals with circulatory brain hypoxia (ischemia) to ILLLR reduced the level of chromosome aberrations in corneal epitheliocytes and led to change in the mitotic index. Correction of the damaging effects of ischemia in the experiment in the absence of mutagenic effect of ILLLR in therapeutic dose and mode of exposure indicates the possibility of applying this physical method for correcting after-effects of oxidative stress during progression of degenerative eye diseases in ophthalmic practice.

[Method of onabotulinumtoxin type A injection in chronic migraine: the PREEMPT protocol in clinical practice]. / Metodika in"ektsii onabotulotoksina tipa A (Botoks) pri khronicheskoi migreni ­ protokol PREEMPT v real'noi praktike.

Chronic migraine (CM), a condition where patients experience over 15 days of headache per month, was identified as a separate disease in the International Classification of Headache Disorders 3-beta version. Onabotulinumtoxin type A was approved for the treatment of CM in 2010 after the completion of the extensive PREEMPT (Phase III Research Evaluating Migraine Prophylaxis Therapy) clinical program. The efficacy of onabotulinumtoxin type A was demonstrated in numerous studies in CM and medication-overuse headache. The paper focuses on the PREEMPT injection paradigm and provides guidance for successful and safe treatment of CM.

[Migraine burden and clinical inertia: what can we do?] / Migren' i klinicheskaia inertsiia: chto my mozhem sdelat'?

AIM: To study the compliance of neurologists and headache specialists to chronic headache and chronic migraine (CM) diagnosis and treatment guidelines. MATERIAL AND METHODS: The survey included 634 neurologists from all regions of the Russian Federation. Mean age of respondents was 40.7±8.5 years, mean years of experience 14.2±7.8 years. RESULTS: Most doctors work in outpatient or hospital settings (49% and 24%, respectively), 7% were headache specialists. Tension-type headache (TTH) was diagnosed in 30% and CM in 17% of patients while 44% of patients were presumed to have a mixed headache disorder (TTH+CM). Only 10% of physicians do not use instrumental diagnostic methods in chronic headache. This study has shown sufficient attention to comorbid conditions and frequent prescription of headache preventative treatment. Botox prescription data is equivocal: 35% of physicians recommend such treatment, 27% do not, while other doctors prescribe it for off-label indications. CONCLUSION: To overcome clinical inertia, further education in chronic headaches and their optimal treatment is warranted.

[Real-world migraine burden: clinical and economic aspects]. / Bremia migreni v real'noi klinicheskoi praktike: klinicheskie i ékonomicheskie aspekty.

AIM: To evaluate the rationale for different approaches to preventive chronic migraine (CM) treatment by comparing clinical outcomes and financial burden of the disease in the real-world practice. MATERIAL AND METHODS: Sixty-six patients with CM were enrolled at the Alexander Vein Headache Clinic (60 women and 6 men, aged 28-51). All patients were divided into 3 groups: group 1 (n=22) received oral preventative treatment with topiramate, up to 100 mg daily, for three months; group 2 (n=20) received 12 acupuncture sessions (3 sessions a week); group 3 (n=24) received 155-195 units of botulinum toxin type A (botox, BTA). The follow-up period in all groups was 3 months. Efficacy was evaluated by clinical examination, the Headache Impact Test (HIT-6) and questionnaires to assess subjective patient satisfaction and treatment tolerability. RESULTS: BTA demonstrated the highest efficacy in this study. Compared to the oral preventative treatment and acupuncture, BTA reduced the frequency of headache faster and more significantly facilitating CM transformation into episodic migraine (headache frequency was 16.1±0.1; 18.0±0.02; and 13.9±0.3 in groups 1, 2 and 3, respectively, after one month of treatment). BTA also improved the quality of life faster and more significantly and was better tolerated (good - 51%, 75% and 85% in groups 1, 2 and 3, respectively; satisfactory - 35%, 25% and 15% in groups 1, 2 and 3, respectively; bad 14% in the oral prevention group). In the BTA group, the majority of patients demonstrated earlier treatment satisfaction. Despite higher (compared to topiramate) direct costs in the BTA group (RUB 29 931.51 and RUB 32 085.87, respectively), the predicted cost of a headache-free day was the smallest and totaled RUB 652.15 (compared to RUB 692.86 and RUB 1017.60 in the topiramate and acupuncture groups, respectively). CONCLUSION: The data on the efficacy and costs of different CM prevention strategies would facilitate optimal treatment choice for neurologists and patients.

[Efficacy of different doses of botox in treatment of chronic migraine]. / Éffektivnost' raznykh doz preparata botoks pri lechenii khronicheskoi migreni.

AIM: To compare the efficacy of botox used in doses of 155 U and 195 U for preventive treatment of chronic migraine (CM). MATERIAL AND METHODS: Thirty-nine women with CM were stratified into two groups according to the dose of botox. The duration of the study was 9 month, patient's state was assessed before treatment and after repeated injections (every 3 month). RESULTS AND CONCLUSION: With regard to the frequency of migraine attacks, the 1st and 2nd injections of botox were equally effective. After the 3rd injection, the frequency was significantly lower in group 2 (195 U). After 2nd and 3rd injections, an effect on patient's adaptation assessed with the MIDAS and patient's satisfaction with treatment were higher. The results suggest the dose-dependent efficacy of repeated injections of botox. The dose of 195 U can be recommended in preventive treatment of CM as more effective.

[Analysis of the efficacy of reflexology in the complex treatment of chronic migraine]. / Analiz éffektivnosti refleksoterapii v kompleksnom lechenii khronicheskoi migreni.

AIM: To evaluate the effect of different reflexology techniques on main clinical indices of patients with chronic migraine, the number of analgesics used and dynamics of chronic migraine comorbid disorders. MATERIAL AND METHODS: The study included 84 patients (60 women (71.5%) and 24 men (28.5%)), aged from 18 to 63 years, with a diagnosis of chronic migraine. Patients were randomized in 4 groups - Su Jok (n=22), acupuncture (n=22), electroacupuncture (n=20), control (n=20). Topiramate was administered in all groups in dose of 100 mg daily. Patients were evaluated before treatment, after 4 and 16 weeks from randomization. RESULTS: There was a marked regression in frequency of headache in reflexological groups in comparison with the control. The number of days with headache was 19±1.12 at baseline and 6.57±1.3 days after treatment in the Su Jok group; 21.6±1.688 and 7±1.786 days in the acupuncture group; 20.25±1.97 and 5.75±0.633 days in the electroacupuncture group. Each of the methods had an impact on various clinical aspects of chronic migraine and comorbid disorders: Su Jok was most effective in treatment of autonomic disorders, the use of acupuncture resulted in the significant reduction of headache intensity and regression of anxiety disorders. The electroacupuncture group showed a significant increase in pain threshold and the least number of days with headache per month. CONCLUSION: Reflexotherapy is a method of choice in the complex treatment of patients with chronic migraine. Taking into account complex diagnosis, the individually oriented approach in prescribing of different reflexology techniques for successful treatment and subsequent rehabilitation of patients with chronic migraine is required.

[Diagnosis and treatment of migraine: Recommendations of the Russian experts]. / Diagnostika i lechenie migreni: rekomendatsii rossiiskikh ékspertov.

These recommendations on the diagnosis and treatment of migraine were elaborated by Russian headache experts in accordance with the evidence-based practice. Together with the latest classification, diagnostic principles and criteria of different clinical sub-forms the consensus contains basic data on migraine epidemiology, pathophysiological mechanisms, differential diagnosis and most effective and evidence based approaches to pharmacological and non-pharmacological management of migraine patients.

[Tanakan as a multimodal cytoprotective factor in general medicine].

The first section of the review provides recent results regarding the mechanism of the action of a standardized extract of ginkgo biloba leaves EGb761 (tanakan), its effects on apoptosis, neuroplasticity, hemorheology, inhibition of the amyloid genesis and inflammatory response it cause, activation of proteasomes in conformational diseases. Current experimental and clinical results suggest that EGb761 (tanakan) is a high-effective cytoprotective agent in cognitive disorders of various genesis, cardiovascular diseases (in the process of rehabilitation and as a medicine capable to reduce the volume of brain damage in stroke). The effect of tanakan on anxiety and depression in patients with cognitive impairment should be considered as clinically significant.

[Strategies on the improvement of chronic migraine treatment efficacy].

OBJECTIVE: To determine the efficacy of type A botulinum toxin (lantox) in the treatment of chronic migraine. MATERIAL AND METHODS: Authors examined 22 patients with chronic migraine at baseline and 4 and 12 weeks after the introduction of 150 U of lantox in head and cervical muscles using "follow the pain method". The drug was introduced into the following muscles: m. corrugator, m. procerus, m. frontalis, m. temporalis and m. оccipitalis. Clinical/neurological examinations, a study of the emotional sphere (anxiety and depression), daily activities, quality-of-life, patient's completion of questionnaires on the subjective satisfaction with treatment were carried out. RESULTS AND CONCLUSION: There was a significant positive effect of treatment on the frequency of headache attacks that was important for reverse transformation of chronic pain to episodic headache. Barriers in compliance may be overcome by solving psychological problems, in particular, overcoming depression. The prescription of the drug with no side-effects and fast results allows to support the adherence of the patient to treatment.

[Tanakan as a multimodal cytoprotective factor in general medicine (part II)].

The second section of the review provides an update of the data on mechanisms of action of a standardized extract of Ginkgo biloba EGb761® (tanakan) and its efficacy in treatment of depression, pain, complications of diabetes, Parkinson disease, tinnitus and dizziness, reproductive dysfunction. Updated data enable to use EGb761® (tanakan) as a highly-effective cytoprotective agent in treatment of cardiovascular, degenerative and metabolic diseases of the nervous system, inner ear disturbances (tinnitus), dysfunction of reproductive system as well as in prevention and treatment of stress-induced disorders.

[Tanakan in the treatment of cognitive and autonomic impairments and headache in young patients].

OBJECTIVE: To determine the efficacy and tolerability of tanakan in the treatment of memory and attention impairments in young patients. MATERIAL AND METHODS: We studied 30 outpatients (24 women and 6 men, mean age 33,5±7,5 years) with headache, memory and attention impairments and decrease in mental working capacity. Treatment duration was 90 days. Patients received tanakan in dose 40 mg 3 times per day to restore cognitive function. The study design included 4 visits during which patients completed questionnaires and scales. RESULTS: All patients reported positive changes in mood, memory, information learning and working capacity. Headaches of tension decreased by 50%, vertigo and noise in ears became less intense, autonomic disturbances practically disappeared. No effect on the frequency of migrainous attacks was found. CONCLUSION: Tanakan is effective and safe for symptomatic therapy of cognitive impairment in any age, including young patients.

[Clinical features of headache of tension type and principles of treatment].

We examined 140 patients, aged from 23 to 47 years, with headache of tension type (HAT). Patients were stratified into two groups: HAT with trigger zones in pericranial muscles (HAT-1) and HAT without those (HAT-2). The study included the detection of pain threshold and pain tolerability in pericranial muscles using pressure algometer, quantitative assessment with the McGill Pain Questionnaire, evaluation of depression and anxiety. Loci of primary and secondary hyperalgesia, signs of anxiety disorder were observed in patients with HAT-1. Diclofenac sodium had a temporary effect and tizanidine had a stable positive effect. In patients with HAT-2, we found loci with signs of secondary hyperalgesia in pericranial muscles and symptoms of depression. There was no effect of diclofenac sodium, tizanidine had a subtle positive effect and venlafaxine exerted a good stable effect. In conclusion, there are different pathophysiological mechanisms of HAT with the presence of trigger zones in pericranial muscles and HAT without trigger zones.

[New approaches to the treatment of chronic daily headache].

Two groups of patients with chronic daily headache have been treated: 16 patients of the first group received katadolon (flupirtin) in dose 300 mg per day during 2 months as an alternative analgesics instead of combined sedative drugs (sedalgin, pentalgin, citramon) that patients abused for many years. The withdrawal period was painless, the use of katadolon resulted in the reduction of attack frequency and the decrease in the amount of traditional analgesics. Katadolon was well tolerated, only two patients reported the total weakness and 1 patient reported diarrhea. Velafax (venlafaxine) in dose 75 mg per day was prescribed to 18 patients of the 2nd group during 6 weeks. The treatment resulted in the decrease of attack frequency and pain intensity. Velafax reduced allodynia which was studied using algometria and touches, and wind-up phenomenon. There was the significant increase of the R3 component of nociceptive blink reflex threshold and pain threshold of nociceptive flexor reflex that indicates the augmentation of antinociceptive protection and decrease in the sensitization of central nociceptive neurons of the trigeminal nerve. Patients treated with Velafax experienced nausea, constipation, impairment of sustained attention, decrease of appetite however these side-effects were mild and passed without treatment during 5-7 days.

[Use of katadolon in the treatment of abuse headache].

Katadolon (flupirtine), an analgetic with neuroprotective and myorelaxing effect, has been used in the treatment of 16 patients (15 women, 1 man, mean age 38 +/- 6 years) with abuse headache. The diagnosis has been established in accordance with International Classification of Headache Disorders, 2nd Revision (2003). All the patients had episodic headache of tension in anamnesis. Chronic pain and significant tension of pericranial muscles have been registered before the treatment. Patients abused complex analgesics, mean amount of which was 24.5 +/- 6.1 during the period of 21.25 +/- 4 days per month. Monotherapy with katadolon was administered in dosage 100 mg 3 times a day during 1 month. The treatment resulted in significant reduction of frequency, duration and intensity of headache, with a 2-fold decrease in analgesics used. The tension of pericranial muscles decreased and threshold of pain as well as that of nociceptive flexor reflex increased. There was improvement of the patients' quality of life. The period of withdrawal from drug abuse was painless. An effect of treatment remained during 1 month after the withdrawal from the drug in 11 patients, 2 patients continued to receive katadolon.

[Use of acupuncture in the therapy of chronic daily headache]. / Primenenie akupunktury v terapii khronicheskoi ezhednevnoi golovnoi boli.

To determine efficacy of acupuncture (AC) in combined treatment of chronic daily headache (CDHA), 90 patients with this disorder were studied, using clinico-neurologic tests. Severity of patient's state was evaluated with Clinical Global Impression (CGI) scale, including scoring of disease severity, global evaluation of the post treatment state dynamics and the index of therapeutic efficacy. Headache intensity was assessed with VAS. A state of functional activity of nociceptive and antinociceptive systems was studied, using nociceptive flexor reflex (NFR). For treatment, the patients were randomly divided into two clinically matched groups: group 1 received combined drug therapy, group 2--combined drug therapy and additional acupuncture course. The results revealed high efficacy of AC combined with drug therapy for CDHA treatment. Most efficient was use of AC in patients with significantly reduced activity of antinociceptive systems and presence of drug abuse allowing to reduce analgetics withdrawal time. Besides, more pronounced clinical effect of AC was obtained in patients with transformed migraine.